Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart

Sandhu, Gurfateh Singh; Burrier, Althea; Janero, David R.

doi:10.1152/ajpheart.1993.265.4.h1249

Cited by 21 publications

(15 citation statements)

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“…The primary advantage of this approach is that the potentiation of extracellular adenosine levels may be restricted primarily to those sites where endogenous extracellular adenosine formation is greatest, for instance in hypoxic/ ischemic tissue or where excessive stimulation occurs. 192,193 Moreover, it has been suggested that inhibition of adenosine deaminase may provide bene®cial effects in older hypertensives, hence, the use of extracellular adenosine deaminase inhibitors may offer cardiovascular protection in hypertension. 183±185 The results of these studies indicated that the pharmacological potentiation of the formation of endogenous extracellular adenosine in response to excitatory aminoacid receptor stimulation may have important therapeutic potential for treating seizure, excitotoxicity, and neurodegenerative disorders.…”

Section: F Potential Therapeutic Use Of Ada Inhibitorsmentioning

confidence: 99%

Adenosine deaminase: Functional implications and different classes of inhibitors

Cristalli¹,

Costanzi²,

Lambertucci³

et al. 2001

Med. Res. Rev.

296

250

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Section: F Potential Therapeutic Use Of Ada Inhibitorsmentioning

confidence: 99%

Adenosine deaminase: Functional implications and different classes of inhibitors

Cristalli¹,

Costanzi²,

Lambertucci³

et al. 2001

Med. Res. Rev.

296

250

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“…Extracellular adenosine interacts in many tissues with specific membrane receptors and exerts various physiological effects. In heart it is a negative chronotrope and negative inotrope, dilates the coronary arterioles, inhibits the leukocyte-endothelium interaction and protects the myocardium against ischaemic damage (Berne 1980;Hori and Kitakaze 1991;Ely and Berne 1992;Toombs et al 1992;Sandhu et al 1993). The concentration of extracellular adenosine in heart increases whenever there exists an imbalance between oxygen demand and oxygen supply, for instance in hypoxia, during increased pacing and during stimulation by catecholamines (Borst and Schrader 1991;Deussen and Schrader 1991;Dobson 1987, 1993;Fenton et al 1990;Gorman et al 1992;Sparks and Bardenheuer 1986;Van Belle et al 1987;Kitakaze et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Ecto-5?-nucleotidase is expressed by pericytes and fibroblasts in the rat heart

Mlodzik

Loffing

Hir

et al. 1995

Histochem Cell Biol

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Ecto-5'-nucleotidase is anchored at the outer surface of cell membranes and thus its reaction product adenosine is released into the extracellular space. Extracellular adenosine displays via specific receptors a wide range of physiological effects in heart. There are discrepancies in the literature concerning the distribution of ecto-5'-nucleotidase in heart. Since we suspected that these may be due to technical problems, in the present study on ecto-5'-nucleotidase in rat heart we attempted to circumvent some technical pitfalls. Good preservation of the tissue with open capillary lumina, providing a clear identification of endothelium, was obtained by perfusion fixation. At the light microscopic level, the distribution of ecto-5'-nucleotidase studied by enzyme histochemistry and immunohistochemistry using a monoclonal and a polyclonal antibody yielded congruent results. The enzyme was rather homogeneously distributed throughout the myocardium, with a slightly higher incidence of stained cells in the outer thirds than in the inner third of the wall. Consistently high levels of ecto-5'-nucleotidase were seen only in interstitial cells. The walls of large vessels and heart muscle cells were constantly negative for ecto-5'-nucleotidase. The endothelia of capillaries were mostly negative but a few profiles occasionally displayed a weak immunoreaction. The interstitial cells staining positive for ecto-5'-nucleotidase could be identified as pericytes and as fibroblasts according to their shapes and localizations. The immunoreactivity of fibroblasts was confirmed by electron microscopy. These data indicate that adenosine may be formed extracellularly in the interstitium of the myocardium, where it would have direct access to important targets such as myocytes, arterioles and nerve endings.

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“…Adenylate deaminase (AMP deaminase, AMP aminohydrolase; EC 3.5.4.6) is a ubiquitous enzyme catalysing the essentially irreversible deamination of 5'-AMP to equimolar amounts of IMP and ammonia [1]. Although particularly critical to adenylate salvage in working skeletal muscle as a component of the purine nucleotide cycle [2], adenylate deaminase in heart muscle appears to support the adenine nucleotide catabolism associated with disease states such as myocardial ischaemia [3,4]. Furthermore, by competing with 5'-nucleotidase (5'-ribonucleotide phosphohydrolase, EC 3.1.3.5) for available AMP, cardiac adenylate deaminase may modulate the local production of adenosine, a cardioprotective mediator of vascular and cardiomyocyte function [4,5].…”

Section: Introductionmentioning

confidence: 99%

Cardiac adenylate deaminase: molecular, kinetic and regulatory properties under phosphate-free conditions

Thakkar¹,

Janero²,

Sharif³

et al. 1994

Biochemical Journal

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Adenylate deaminase (EC 3.5.4.6) may help to regulate the adenine nucleotide catabolism characteristic of such disease states as myocardial ischaemia. We report analysis of the molecular, kinetic and allosteric properties of rabbit heart adenylate deaminase when extracted and purified under phosphate-free conditions (i.e., with Hepes/KOH). The enzyme's subunit molecular mass (approximately 81 kDa), pI (6.5), substrate specificity for 5'-AMP, and activation by K+ were identical in the absence or presence of phosphate. At each chromatographic step during isolation without phosphate, cardiac adenylate deaminase showed a lower apparent activity as compared with the enzyme prepared with phosphate present. Kinetic constants for the phosphate-free rabbit heart adenylate deaminase preparation (Km 0.54 mM AMP; Vmax. 1.4 mumol/min per mg of protein) were approximately 10-fold lower than those of the enzyme isolated with phosphate. The same irreversible decrease in kinetic constants could be achieved by dialysing phosphate from the phosphate-containing enzyme preparation. The relationship between enzyme activity and substrate concentration was sigmoidal in the presence of phosphate, but hyperbolic in its absence. Cardiac adenylate deaminase under phosphate-free conditions was no longer allosterically activated by ATP and ADP, yet remained inhibitable by GTP. Enzyme inhibition by the transition-state mimic coformycin was not influenced by phosphate status. The phosphate-free preparation of rabbit heart adenylate deaminase was markedly labile and extremely susceptible to proteolysis by trypsin or chymotrypsin. The inactivation kinetics and fragmentation pattern in response to controlled proteolysis depended on whether the enzyme had been isolated with or without phosphate present, suggesting a conformational difference between the two enzyme preparations. These data constitute direct evidence that the absence of phosphate irreversibly converts cardiac adenylate deaminase into a pseudo-isoenzyme with distinct kinetic, regulatory and stability properties.

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Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart

Cited by 21 publications

References 0 publications

Adenosine deaminase: Functional implications and different classes of inhibitors

Adenosine deaminase: Functional implications and different classes of inhibitors

Ecto-5?-nucleotidase is expressed by pericytes and fibroblasts in the rat heart

Cardiac adenylate deaminase: molecular, kinetic and regulatory properties under phosphate-free conditions

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